Gliomas are brain tumors that arise from glial or precursor cells. Of the 70,000 new cases of brain tumors a year, 30% are gliomas. Malignant gliomas in the form of anaplastic astrocytoma and glioblastoma are aggressive tumors characterized by high proliferation and invariably lead to a poor prognosis. In glioblastoma, of which there are 10,000 cases a year in the United States, the average survival without treatment is less than six months. Aggressive treatment with surgery, chemotherapy, and radiotherapy, can extend survival to a year. The poor clinical outcomes for malignant gliomas emphasizes the need for new therapeutics to combat this disease. Sequencing these malignant gliomas has revealed shared characteristics for some of these tumors. Common genetic lesions include amplification of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) and deletion of tumor suppressor genes such as Ink4a/Arf and Pten. Ligands for EGFR are also found commonly co-amplified in these tumors including heparin-binding EGF-like growth factor (HBEGF). Querying the Cancer Genome Atlas (TCGA) database, the result of a systematic approach to characterize glioblastoma in several dimensions including gene expression and clinical treatment information, shows that patients whose tumors have increased expression of HBEGF had decreased survival. This correlation was not observed in other related EGF ligands. In addition, previous studies have shown HBEGF expression by immunohistochemistry and RT-PCR in up to 40% of malignant gliomas. In other types of tumors, HBEGF increases proliferation and tumor invasion, but this has not yet been characterized in brain tumors. In light of the TCGA data and available literature, this proposal seeks to address key questions about the sufficiency of HBEGF in tumorigenesis, the signaling pathways of HBEGF in astrocytes, and the necessity of HBEGF for tumor maintenance. Key methods used to complete these aims include a glioma model based on retroviral gene delivery, gene editing, in vivo conditional gene expression, and high-throughput sequencing. Successful completion of the aims will not only elucidate the key roles that HBEGF plays in gliomas but also provide insight for targeting HBEGF as a new therapeutic tool.